The isolation of combretastatin A-4 was disclosed in U.S. Pat. No. 4,996,237 to George R. Pettit et al. issued Feb. 26, 1991. The general background therefrom relating to combretastatin A-4 is incorporated herein, by this reference thereto, as if fully set forth.
The potent cancer cell growth (Von Hoff et al., 1993 and tubulin assembly (Hamel et al., 1989) inhibitor combretastatin A-4 (1) (Pettit et al., 1989) isolated from the African tree Combretum caffrum (Combretaceae) has been undergoing preclinical development. Due to the very sparing aqueous solubility behavior of phenol 1a and its alkali metal salts (cf, 1b, c) drug formulation attempts gave unsatisfactory results. This invention relates to the synthesis of a practical water soluble pro-drug.